Project Summary Brain-derived neurotrophic factor (BDNF) is a chief regulator of excitatory synaptic plasticity, and diminished function of this neurotrophin is associated with obesity and metabolic dysfunction in humans and rodents. We showed that mice with global central BDNF depletion (BDNF2L/2LCk-cre) exhibit obesity, insulin resistance, hyperglycemia and dyslipidaemia. These findings have significant clinical implications as the BdnfVal66Met variant, which interferes with BDNF signaling, is highly prevalent in humans. Previous findings indicate that the ventromedial hypothalamus (VMH), a critical region for energy and glucose balance control, is an important site of BDNF action. The mechanisms underlying the effects of BDNF are poorly defined, especially those acting independently from feeding control. This proposal will investigate the novel role of metabotropic glutamate receptor 5 (mGluR5) mediating effects of BDNF on VMH neuronal activity and glycemic control. It emanates from our discovery that mGluR5 expression is significantly reduced in VMH of BDNF2L/2LCk-cre mutants. mGluR5 is highly expressed in the VMH and present in neurons (including SF1+) and astrocytes in this region and plays paramount roles in excitatory synaptic plasticity in the adult brain. Notably, we found that selective deletion of mGluR5 in VMH SF1+ neurons significantly impaired glycemic control and lipid metabolism without affecting body weight in mutant (mGluR5f/f:SF1-cre) female but not in male mice. Thus, we hypothesize that mGluR5 acts downstream of BDNF to mediate glucose and lipid homeostasis in a weight-independent and sex-specific manner by elevating the excitatory tone of SF1+ neurons. Aim 1 will test the hypothesis that sex-specific effects of mGluR5 in SF-1+ neurons involve functional interactions with estrogen receptors (ER). Aim 2 consists of anatomical, electrophysiological and molecular studies ascertaining the sex-specific role of mGluR5 regulating activity of SF1+ neurons, Aim 3 will define molecular mechanisms in SF1+ neurons governed by ER-mGluR5 interactions to control neuronal activity and glucose and lipid homeostasis and Aim 4 will test whether effects of BDNF on metabolic function are mediated by mGluR5-ER functional interactions in females. In aggregate, these investigations will inform novel mechanisms mediating glucose homeostasis and new avenues to tackle diabetes and its associated medical complications. In particular, it will inform the higher risk of insulin resistance and metabolic disorders reported in post menopausal women.